Stable solutions of metal complex compounds



Patented Aug. 23, 1932 m'rso STATES PATENT OFFICE HANS SCHMIDT, OFWUPPERTAL-VOHWINKEL, GERMANY, ASSIGNOR TO WIN'I'HBOP NEW YORK, N. Y., ACORPORATION OF NEW YORK CHEMICAL COMPANY, INC., OF

STABLESOLUTIONS OF METAL COMIPLEX COMPOUNDS No Drawing. Applicationfiled April 18, 1931, Serial No. 529,889,

The present invention relates to stable aqueous solutions of neutralmetal complex compounds of polyoxy benzenes which contain at least twohydroxy groups in orthoposition to each other and at least one car"-boxylio or sulfonic acid group.

It is known that stable injection solutions can be obtained from metalcomplex salts of Polyhydroxy benzenes containing at least two hydroxygroups in the ortho-position and containing acid-salt-forming groups,but the standardization of these solutions to a neutral reaction isconfined to certain limits,

cause as soon as the solution becomes weakly alkaline discoloration ofthe solution mostly takes place. This discoloration can, for example,already occur when injection solutions are standardized to a pH range ofabout 6.5 to 7.5, which range is suitable for injection purposes. Thesame discoloration is mostly observed during the sterilization of thesaid solutions.

In accordance with the present invention, aqueous solutions of thealkali salts of complex compounds of a heavy, therapeutically activemetal'of the group consisting of anti- 1 pH range of about 6.5 to 7.5

mony, arsenic, manganese and bismuth with a polyhydroxy benzene of theprobable formula wherein R stands for hydrogen or a hydroxy group, 2vstands for a carboxylic or sulfonic acid group and R stands for hydrogenor a sulfonic acid r'oup, may be rendered stable, when stored in closedvessels, also when standardizing these solutions to a by adding to thesesolutions derivatives of sulfurous acid. The alkali metalandammonium-sulfites, -bisulfites, -metabisulfites and -acetone bisulfiteshave proved to be especially suitable for the above pu ose. A content ofabout 2 parts per 1000 of these substances is suflicient to prohibit thediscoloration of the complex salt solutions of a pH rangeof about 6.5 to7 even sufliciently stable,

,of dilute caustic soda lye or ammonia.

and in Germany May 10, 1929.

when the solutions are sterilized by heat, so

that by these very small admixtures a remarkable improvement of thestability of the aqueous solutions of the said metal complex compoundsis effected without these solutions having any disadvantage forinjection purposes. It may be mentioned that solutions containing only 1part er 1000 or a still smaller quantity of the sta ilizer have provedalthough a higher content for example, 5 parts per 1000 of thestabilizer,

the preparation is without disadvantage in of the injection solutions.

The invention is further illustrated by the following examples withoutbeing restricted thereto:

Ewample 1 'A 6.3% aqueous solution of antimonyl-pyrocatechol-sodium.disulfonate of the probable formula:

OaNa, SOINB is incorporated in the proportion of 1:1000 with sodiummeta-bisulfite and then the so lution is standardized to a hydrogen ionconcentration '(pH) of 6.8 to 7.5 by the addi tii gn e solution obtainedis then filled into ampoules. When being sterilized by heat, thesolution remains colorless ble when stored.

When using instead of antimonyl-pyrocatechol-sodium disulfonate,antimonyl-pyrocatechol-sodium monosulfonate or antimonylpyrogalloLsodiumdisulfonate, likewise stable, colorless aqueous solutions of the latterof a pH of 6.8 to 7.5, containing 1% of sodium metabisulfite, areobtained which are especially suitable for injection purposes.

The same results are obtained by using instead of sodiumrmetabisulfatethe corresponding quantitiesof potassium or ammonium meta-bisulfite orof sodium, potassiumor ammonium-bisulfites or sulfites or mixtures ofthese substances.

in the ampoules and is sta-.

Example 2 v 6.15 grams of manganese 'pyrocatechol sodium disulfonate and1 gram of sodium metabisulfite are dissolved inone liter of water. Thissolution is standardized to a hydrogen ion concentration of about 7 bymeans of dilute caustic soda lye, filled into ampoules and sterilized.After sterilizing a scarcely colored solution is obtained.

Ewample 3 NaOOO o 20 and 0.2 grams of sodium bisulfite are dissolved inwater, the solution is standardized to a pH of about 7.2, made up to 100ccs., filled into ampoules and sterilized by heat. A light coloredsolution is obtained.

In an analogous manner, the potassium salt ofantimonyl-pyrocatechol-ortho-carboxylic acid can be added to a stableaqueous solution of a pH of about 7.

Example 1} COONB 10 grams of bismuth-pyrocatechol-sodium disulfinate and0.1 gram of sodium bisulfite are dissolved in water. The solution isthen standardized to a pH of about 7 bymeans of dilute caustic potashsolution, filled up to 100 ccs., put into ampoules and sterilized byheat. A light colored solution is obtained.

When using instead of the above bismuth complex salts the correspondingarsenous compounds, an analogous result is obtained.

Complex salts of the different metals mentioned above, mixed with analkali salt of any other complex forming components of the formula B oni Bl wherein R stands for hydrogen or a hydroxy group, R stands for asulfonic or carboxylic acid group and R stands for hydrogen or asulfonic acid group, the production of the stable solutions of suchcomplex compounds not having been specifically described above,- yieldin the same manner the stable solutions without showing any remarkabledifference when compared with the above exam les. i

claim: r

1. Aqueous solutions salts of com of the alkali metal lex compounds of atherapeutically active eavy metal of the group consist- 0 mg ofantimony, arsenic, manganese and hismuth with a polyhydroxy benzene ofthe probable formula:

wherein R stands for hydrogen or a hydroxy group, R stands for an acidsubstituent of the group consisting of the carboxylic and sulfonic acidgroups and R stands for hydrogen or a sulfonic acid group, saidsolutions being characterized by a hydrogen ion concentration of about6.5 to 7.5 and by a small content ofa sulfurous ac'd derivative of thegroup consisting of alkali monium-sulfites, -bisulfites, -metabisulfites and acetonebisulfites, said solutions being stable whenfilled in closed vessels and showifiig no discoloration even whensterilized by eat.

2-. Aqueous solutions of the alkali metal salts of complex compounds ofa therapeutically active heavy metal of the group consisting ofantimony, arsenic, manganese an bismuth with a polyhydroxy benzene ofthe probable formula:

R OH

wherein R stands for hydrogen or a hydroxy stands for group, R an acidsubstituent of the group consisting of the carboxylic and 2 stands forliy- 3. Aqueous solutions of the alkali metal salts of complex compoundsof a therapeutically active heavy sisting of antimony, arsenic,manganesean bismuth with a polyhydroxy benzene of the probable formula:

wherein R stands for hydrogen or a hydroxy group, said solutions beingcharacterized by a hydrogen ion concentration of about 6.5 to 7.5 and bya small content of a sulfurous acid derivative of the group consistingof alkali metaland ammonium-sulmetaland ammetal of the group conlites,-bisulfites -metabisulfites and acetonebisulfites, said solutions being,stable when filled in closed vessels and showing no discoloration evenwhen sterilized by heat.

4. Aqueous solutions of the alkali metal salts of complex compounds ofantimony with a polyhydroxy benzene of the probable formula:

HO: 0B

wherein R stands for hydrogen or a hydroxy group, said solutions beingcharacterized by a hydrogen ion concentration of about 6.5 to 7.5 and bya small content of a sulfurous acid derivative of the group consistingof alkali metalammonium-sulfites, -bisulfites, -metal bisulfites andacetonebisulfites, said solutions being stable when filled in closedvessels and showing no discoloration even when sterilized by heat.

5. queous solutions of the alkali metal salts of complex compounds of atherapeutically active heavy metal of the group consisting of antimony,arsenic, manganese and bismuth with a polyhydroxy benzene of theprobable formula:

wherein R stands for hydrogen or a hydroxy group, R stands for an acids'ubstitu ent of the group consisting of the carboxylic and sulfonicacid groups and R stands for hydrogen or a ,sulfonic acid group, saidsolu tions bein characterized by a hydrogen ion concentratlon of about6.5 to 7.5 and by the content of '1-5 parts per 1000 of a sulfurous R onwherein R stands for hydrogen or a hydroxy group, R stands for an acidsubstituent of the group consisting of the carboxylic and sulfonic acidgroups and R stands for hydrogen or a sulfonic acid group, saidsolutions being characterized by a hydrogen ion concentration of about6.5 to 7.5 and by the content of 1-5 parts per 1000 of a sulfuric acidderivative of the group consisting of 1allkali metalandammonium-sulfites, -b1sul tes said solutions being stable when filled inmetabisulfit-es and acetonebisulfites,

closed vessels and showing no discoloration V 1 even when sterilized byheat. 7

7. Aqueous solutions of the alkali metal salts of complex compounds of atherapeutically active heavy metal of the group consisting of antimony,arsenic, manganese and bismuth with a polyhydroxy benzene of theprobable formula:

R033 OH SOaH wherein R stands for hydrogen or a hydroxy group,.saidsolutions being characterized by a hydrogen ion concentration of about6.5 to 7.5 and by the content of 1-5 parts per 1000 of a sulfurousacidderivative of the group consisting of alkali metaland ammonlum-sulfites,-bisulfites, -metabisulfites and ace-tonebisulfites, said solutionsbeing stable when filled in closed vessels and showing no discolorationeven when steri lized by heat.

8. Aqueous solutions of the alkali metal salts of complex compounds ofantimony with a polyhydroxy benzene of the probable formula: 7

Hoes OH wherein R stands for hydrogen or a hydroxy group, said solutionsbeing characterized by a hydrogen ion concentration of about 6.5 to 7.5and by the content of 1-5 parts per 1000 of a sulfurous acid derivativeof the groupconsisting of alkali metalammonium-sulfites, -bisulfites,-metabisulfites and acetonebisulfites, said solutions being stable whenfilled in closed vessels and showing no discoloration even whensterilized by heat.

9. Aqueous solutions of the antimony complex compound of the probableformula:

N80; OzNB 'said solu tions being characterized by a bydrogen ionconcentration of about 6.8 to 7 .5 and by a content of about 1 part per1000 of sodium metabisulfite, said solutions being stable when filledinto closed vessels and showing no discoloration even when sterilized byheat.

10. Aqueous solutions of the antimony complex compound of the probableformula:

moas I o o soma Y OBNa OaNB containing about 6.3% of the said complexcompounds, said solutions being characterized by a hydrogen ionconcentration of about 6.8 to 7.5 and by a content of about 1 part per1000 of sodium metal-bislulfite, said solutions being stable when filledinto closed vessels and showing no discoloration even when sterilized byheat.

11. Aqueous solutions of the antimony complex compound of the probableformula:

said solutions being characterized by a hydrogen ion concentration ofabout 6.8 to 7.5 and by a content of about 1 part per 1000 ofsodiummetabisulfite, said solutions being stable when filled into closedvessels, showing no discoloration even when sterilized by heat. v I

In testimony whereof, I afiix my si nature.

. HANS SCHMIDT.

